This invention relates generally to an animal model for preeclampsia that mimics the pathophysiology and etiology of the disease in humans.
Preeclampsia, the most prevalent hypertensive disorder of pregnancy, is defined by the triad of hypertension, proteinuria, and edema. It is thought to impact 6–10% of pregnancies and is the leading cause of maternal mortality in Western countries. Great Britain Department of Health, WHY MOTHERS DIE: REPORT ON CONFIDENTIAL ENQUIRIES INTO MATERNAL DEATHS IN THE UNITED KINGDOM 1994–1996. London; TSO (1998). A distinguishing feature of the disorder is its complete resolution following delivery of the fetus and placenta—the only known effective means to avoid cataclysmic progression to overt eclampsia. The necessity for urgent preterm delivery, along with progressive intrauterine growth restriction implicate preeclampisa as a leading cause of perinatal morbidity and mortality. National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy, Am. J. Obstet. Gynecol. 163:1691–1712 (1990). Hospitalization, strict bed rest, magnesium sulfate administration to prevent convulsions, and prompt delivery are the current standard of therapy for preeclampsia.
Despite its prevalence the exact cause of preeclampsia remains unclear. Current postulated theories include a primary causative role for the placenta, poor placental perfusion resulting in hypoxia and increased oxidative stress, Roberts et al. Lancet 354:788–789 (1999), an exaggerated activation of the maternal immune response, Chun et al., Obstet Gynaecol Br Commonw 71:180–184 (1964), and maternal predisposition due to underlying disorders associated with microvascular disease. The contribution of the placenta is evident from the findings that preeclampsia can develop in pregnancies without a fetus i.e., hydatidiform mole, (Chun et al., Obstet Gynaecol Br Commonw 71:180–184 (1964)), in pregnancies outside the uterus, (Piering et al., Am J Kid Dis 21:310–313 (1993)), and perhaps more importantly delivery, which removes this causative organ results in complete remission of the symptoms associated with preeclampsia. The link between reduced placental perfusion and the eventual manifestations of hypertension and renal dysfunction appears to be the release of a damaging factor(s) from the placenta that leads to widespread dysfunction of the maternal vascular endothelium. Alexander et al., News Phys Sci 16:282–286 (2001); Roberts et al., Am. J. Obstet. Gynecol. 161:1200–1204 (1989). Other studies have suggested a primary maternal vascular disorder with reduced organ perfusion secondary to vasospasm and activation of the coagulation cascade. Roberts et al., Am J Hypertens 4:700–708 (1991).
Timely expansion of the placental vasculature at the feto-maternal interface with appropriate perfusion appears be critical to the normal development and survival of the fetus. In the hemochorial human placenta the maternal blood perfuses a space lined by syncytiotrophoblasts that form the outer layer of the floating chorionic villi. The underlying stem cell cytotrophoblasts also differentiate into extravillus cells that display an invasive phenotype as they migrate along the cell column into the endometrium, inner-third of the myometrium and towards the spiral arteries. The replacement of the laminar smooth muscle of these maternal spiral arteries by the invading cytotrophoblasts results in marked dilatation of the arteries and increases blood supply to the expanding placenta. Most of these physiological changes are completed in the first half of gestation, although clinical manifestations of any dysregulation are usually seen later in pregnancy, as with preeclampsia. Recent data obtained from human placental biopsies have focused attention on abnormal cytotrophoblast-decidual interactions as a central culprit in the development of preeclampsia. Brosens et al., Obstet Gynecol Annu, 1:177–191 (1972); Zhou et al., J Clin Invest 99:2152–2164 (1997); Caniggia et al., J Clin Invest 103:1641–1650(1999). These studies have demonstrated an incomplete invasion of trophoblasts into the uterus and its vasculature (Brosens et al., Obstet Gynecol Annu 1:177–191 (1972)), abnormalities in cytotrophoblast differentiation from an epithelial to endothelial phenotype (Zhou et al., J Clin Invest 99:2152–2164 (1997); Caniggia et al., J Clin Invest 103:1641–1650 (1999)), excess proliferation of immature intermediate trophoblasts (Redline et al., Hum Pathol 26:594–601 (1995)), and reduced expression of genes regulating angiogenesis such as vascular endothelial growth factor (VEGF)-A and its receptor VEGFR-1 (Zhou et al., Am J Pathol 160:1405–1423 (2002)). Although the primary trigger for the above abnormalities remains elusive, these impaired changes can result in decreased flow of oxygenated blood to the feto-placental unit, which in turn can contribute to the compromised fetal growth and low birth-weights observed in pregnancies complicated with severe preeclampsia. Alexander et al., News Phys Sci 16:282–286 (2001).
The preeclampsia/eclampsia syndrome was described by ancient civilizations. Despite considerable research effort to date, we still understand very little about its etiology and pathophysiology, which are complex and multifactorial. Morgan et al., Sem. Perinatol. 23:14–23 (1999). Clinical research is difficult due to the logistics of testing hypotheses related to pathogenesis or treatment in an urgent, high risk setting. Development of an animal model that fully recapitulates this complex hypertensive disorder would help broaden scientists' understanding of this disorder, and would hold great potential for design and implementation of effective prevention and treatment. Podjarny et al., Sem. Perinatol. 23:2–12 (1999).
Women with elevated baseline blood pressure prior to pregnancy have an increased risk for developing preeclampsia. Reiter et al., Am. J. Kid. Dis. 24:883–7 (1994). Understanding the complex mechanisms in the pathogenesis of preeclampsia is limited due to the difficulties in performing studies in pregnant women, and in part due to the lack of an animal model that fully recapitulates the disease. Many attempts have been made to generate animal models of preeclampsia, including uteroplacental ischemia (Losonczy et al., Hypertension in Preg. 12:475–85 (1993); Clark et al., Am. J. Physiol. 242:H297–H301 (1982)), chronic nitric oxide synthase inhibition (Yallampalli et al., Am. J. Obstet. Gynecol. 169:1316–20 (1993)), adriamycin nephropathy (O'Donnell et al., J. Lab. Clin. Med. 106:62–7 (1985)), and transgenic expression of human renin-angiotensin system genes (Takimoto et al., Science 274:995–8 (1996)). Each has been important for understanding certain aspects of the disease, although none recapitulate the full syndrome. Podjarny et al., Sem. Perinatol. 23:2–12 (1999). In most of these models, hypertension does not resolve upon delivery, and pathophysiological changes are observed both in pregnant and non-pregnant animals. Podjarny et al., Sem. Perinatol. 23:2–12 (1999). In view of the foregoing, it would be desirable to generate an animal model that fully recapitulates preeclampsia.